Gene Active in Skeletal Muscle Controls Mice’s Fat Metabolism

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by Forest Ray PhD |

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Skeletal muscle regulates how the body stores and metabolizes fats through the Krüppel-like factor 15 (KLF15) gene, establishing a molecular link between muscle health and conditions such as obesity and diabetes, according to a recent study in mice.

The findings also showed that a diet rich in short-chain fatty acids — obtained from fruits, vegetables, beans and whole grains — protected against weight gain and also facilitated weight loss in mice lacking KLF15 in their muscles.

The study, “Muscle Krüppel-like factor 15 regulates lipid flux and systemic metabolic homeostasis,” was published in the Journal of Clinical Investigation.

Skeletal muscle — that found attached to bones and tendons, and under voluntary control — plays a major role in fat metabolism. Because of this, skeletal muscle dysfunction can disrupt the balance of fats in the body, also called fat homeostasis.

KLF15 has been identified as an important regulator of metabolic processes that take place both within and between diverse organs, and associates with changes in body mass index (a measure of body fat). This prompted researchers at University Hospitals Cleveland Medical Center and Case Western Reserve University School of Medicine to investigate its role in fat storage and metabolism more closely.

The team bred mice that lacked KLF15 in their skeletal muscles and first observed how they developed on a normal diet.

These mice grew obese, developed high circulating levels of fats and sugar, and became insulin resistant (meaning that insulin stopped helping sugar enter cells where it could be metabolized). They also were prone to non-alcoholic fatty liver disease (NAFLD), in which fat accumulates in the liver, where it can cause scarring, fatigue, and weight loss.

“We knew from prior work by our team that the role of KLF15 was critical for muscle health, because levels are increased in humans following exercise,” Mukesh Jain, MD, the study’s senior author, said in a press release.

“Experimentally, muscle loss of KLF15 led to a reduction in exercise capacity in mice. The fact that KLF15 is also important in metabolic health is really exciting as it provides a potential molecular link between exercise and overall health,” Jain said.

To further explore the role of KLF15 in fat metabolism, the researchers fed mice a high-fat diet for 10 weeks. These mice grew significantly obese, exhibited features of diabetes, and developed severe fatty liver deposits.

Alongside the observable changes, the investigators recorded genetic alterations, including those wherein genes needed to metabolize long-chain fatty acids (LCFA) were less active. LCFA cannot enter the mitochondria,  which are cellular organelles responsible for energy production, without first being metabolized into smaller molecules.

As past studies have found that short-chain fatty acids (SCFA) can bypass some of the steps involved in LCFA metabolism and improve both organ function and metabolic health, the team explored the effect that an SCFA-rich diet might have on the mice.

Compared to animals eating the control diet, the SCFA-fed mice showed significantly less weight gain and improved insulin sensitivity, despite continuing to exhibit high blood sugar levels.

To examine the therapeutic potential of an SCFA-rich diet, the scientists fed mice a high-fat diet for five weeks, followed by eight weeks of either a normal or SCFA diet.

Mice switching to the SCFA diet lost more weight than those switching to the normal diet. They also lowered their blood sugar levels and grew less insulin intolerant than their normal diet-fed counterparts.

Collectively, these results demonstrated the vital role that skeletal muscle plays in fat metabolism and liver health, and shows that SCFA-rich diets might help both prevent and treat metabolic diseases caused by impaired fat processing.

“Here,” the researchers concluded, “we show that a primary defect in skeletal muscle (i.e., loss of KLF15) can contribute to increased lipid deposition in distant organs even in the basal (chow-fed) state characterized by mild glucose intolerance and insulin insensitivity, thus offering additional insight as to how skeletal muscle can contribute to the development of metabolic disease.”

The team next plans to explore KLF15’s role in different nutritional states, such as fasting and exercise, and to investigate the therapeutic potential of treatments that target muscle KLF15.

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